U.S. patent number 4,396,772 [Application Number 06/323,859] was granted by the patent office on 1983-08-02 for phosphinylalkanoyl amino acids.
This patent grant is currently assigned to F. R. Squibb & Sons, Inc.. Invention is credited to Edward W. Petrillo, Jr..
United States Patent |
4,396,772 |
Petrillo, Jr. |
August 2, 1983 |
Phosphinylalkanoyl amino acids
Abstract
Angiotensin converting enzyme activity is inhibited by compounds
having the formula ##STR1## and salts thereof wherein R.sub.1 is
alkyl, aryl, arylalkyl, cycloalkyl, or cycloalkyl(alkyl); R.sub.2
and R.sub.4 each is independently hydrogen, alkyl, arylalkyl or
##STR2## wherein X is hydrogen, alkyl, or phenyl and Y is hydrogen,
alkyl, phenyl or alkoxy, or together X and Y are --(CH.sub.2).sub.2
--, --(CH.sub.2).sub.3 --, --CH.dbd.CH--or ##STR3## R.sub.3 is
hydrogen or alkyl; ##STR4## is a residue of an amino acid selected
from the group consisting of glycine, alanine, valine, norvaline,
leucine, N-methylleucine, norleucine, isoleucine, phenylalanine,
tyrosine, serine, threonine, cysteine, methionine, aspartic acid,
glutamic acid, arginine, lysine, asparagine, glutamine, histidine,
or tryptophane; and n is 0 or 1.
Inventors: |
Petrillo, Jr.; Edward W.
(Pennington, NJ) |
Assignee: |
F. R. Squibb & Sons, Inc.
(Princeton, NJ)
|
Family
ID: |
23261036 |
Appl.
No.: |
06/323,859 |
Filed: |
November 23, 1981 |
Current U.S.
Class: |
548/414; 558/170;
987/104; 987/186; 987/180; 548/112; 562/15 |
Current CPC
Class: |
C07F
9/5728 (20130101); C07F 9/301 (20130101); C07F
9/6506 (20130101); C07F 9/3211 (20130101); A61P
9/12 (20180101) |
Current International
Class: |
C07F
9/6506 (20060101); C07F 9/00 (20060101); C07F
9/572 (20060101); C07F 9/32 (20060101); C07F
9/30 (20060101); C07F 009/32 () |
Field of
Search: |
;260/943,52.5G,942
;548/414,112 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Primary Examiner: Sutto; Anton H.
Attorney, Agent or Firm: Levinson; Lawrence S. Barrack;
Donald J.
Claims
What is claimed is:
1. A compound having the formula ##STR18## or a salt thereof,
wherein R.sub.1 is alkyl, aryl, arylalkyl, cycloalkyl, or
cycloalkyl(alkyl);
R.sub.2 and R.sub.4 each is independently hydrogen, alkyl,
arylalkyl or ##STR19## wherein X is hydrogen, alkyl, or phenyl and
Y is hydrogen, alkyl, phenyl or alkoxy, or together X and Y are
--(CH.sub.2)--.sub.2, --(CH.sub.2).sub.3 --, --CH.dbd.CH-- or
##STR20## R.sub.3 is hydrogen or alkyl; ##STR21## is a residue of
an amino acid selected from the group consisting of glycine,
alanine, valine, norvaline, leucine, N-methylleucine, norleucine,
isoleucine, phenylalanine, tyrosine, serine, threonine, cysteine,
methionine, aspartic acid, glutamic acid, arginine, lysine,
asparagine, glutamine, histidine, or tryptophane; and
n is 0 or 1;
wherein the amino acid residue ##STR22## is linked to the adjacent
carbonyl group by an amide bond.
2. A compound in accordance with claim 1 wherein n is 1.
3. A compound in accordance with claim 1 wherein R.sub.2 and
R.sub.4 each is hydrogen.
4. A compound in accordance with claim 1 wherein one of R.sub.2 and
R.sub.4 is hydrogen and the other is ##STR23##
5. The compound in accordance with claim 1
N-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-L-tyrosine, methyl
ester.
6. The compound in accordance with claim 1
N-[[hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-tyrosine, methyl
ester.
7. The compound in accordance with claim 1
N-[[hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-tyrosine.
8. The compound in accordance with claim 1 N.sup.2
-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-L-arginine.
9. The compound in accordance with claim 1 N.sup.2
-[[hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-arginine.
10. The compound in accordance with claim 1
N-[[(2-phenylethyl)(phenylmethoxy)phosphinyl]-acetyl]-L-tryptophan,
phenylmethyl ester.
11. The compound in accordance with claim 1
N-[[hydroxy(2-phenylethyl)phosphinyl]acetyl]-L-tryptophan, ammonia
salt.
Description
RELATED APPLICATION
United States patent application No. 212,911, filed Dec. 4, 1980,
now U.S. Pat. No. 4,337,201, issued June 29, 1982 discloses that
phosphinylalkanoyl substituted prolines and esters of
phosphinylalkanoyl prolines are inhibitors of angiotensin
converting enzyme and are useful in the treatment of
hypertension.
BACKGROUND OF THE INVENTION
The recent literature disclosed a variety of mercaptoacyl amino
acids which are useful for inhibiting the conversion of angiotensin
I to angiotensin II in mammals and are, therefore, useful in the
treatment of hypertension. Also disclosed for the same utility are
phosphinyl alkanoyl prolines.
United States Pat. No. 4,105,776, issued Aug. 8, 1978 discloses
mercaptoacyl amino acids wherein the amino acid is, inter alia,
proline, 4-hydroxyproline and 4-alkylproline.
U.S. Pat. No. 4,112,119 discloses mercaptoacyl amino acids wherein
the amino acid is, inter alia, alanine, leucine, phenylalanine,
arginine, sarcosine, serine, asparagine, lysine, histidine,
glycine, tryptophane, cysteine, methionine, valine, glutamine, or
tyrosine.
U.S. Pat. No. 4,168,267, issued Sept. 18, 1979 discloses
phosphinylalkanoyl prolines, and esters and salts thereof.
BRIEF DESCRIPTION OF THE INVENTION
Compounds having the formula ##STR5## and salts thereof, have
hypotensive activity. In formula I, and throughout the
specification, the symbols are as defined below.
R.sub.1 is alkyl, aryl, arylalkyl, cycloalkyl, or
cycloalkyl(alkyl);
R.sub.2 and R.sub.4 each is independently hydrogen, alkyl,
arylalkyl or ##STR6## wherein X is hydrogen, alkyl, or phenyl and Y
is hydrogen, alkyl, phenyl or alkoxy, or together X and Y are
--(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --CH.dbd.CH-- or
##STR7## R.sub.3 is hydrogen or alkyl; ##STR8## is a residue of an
amino acid selected from the group consisting of glycine, alanine,
valine, norvaline, leucine, N-methylleucine, norleucine,
isoleucine, phenylalanine, tyrosine, serine, threonine, cysteine,
methionine, aspartic acid, glutamic acid, arginine, lysine,
asparagine, glutamine, histidine, or tryptophane; and
n is 0 or 1.
The term "aryl," as used throughout the specification either by
itself or as part of a larger group, refers to phenyl or phenyl
substituted with halogen, alkyl, alkoxy, alkylthio, hydroxy,
alkanoyl, nitro, amino, dialkylamino, or trifluoromethyl groups.
Phenyl and monosubstituted phenyl are preferred and phenyl is the
most preferred.
The term "alkyl," as used throughout the specification either by
itself or as part of a larger group, refers to groups having 1 to
10 carbon atoms. Alkyl groups having 1 to 4 carbon atoms are
preferred.
The term "cycloalkyl," as used throughout the specification either
by itself or as part of a larger group, refers to groups having 3
to 7 carbon atoms.
The term "alkoxy," as used throughout the specification either by
itself or as part of a larger group, refers to groups having 1 to 8
carbon atoms. Alkoxy groups having 1 to 3 carbon atoms are
preferred.
The term "halogen," as used throughout the specification either by
itself or as part of a larger group, refers to fluorine, chlorine,
bromine and iodine. The preferred halogen groups are fluorine and
chlorine.
The term "alkanoyl," as used throughout the specification either by
itself or as part of a larger group, refers to groups having 2 to 9
carbon atoms.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of formula I, and salts thereof, are hypotensive
agents. They inhibit the conversion of the decapeptide angiotensin
I to angiotensin II and, therefore, are useful in reducing or
relieving angiotensin related hypertension. The action of the
enzyme renin on angiotensinogen, a pseduoglobulin in blood plasma,
produces angiotensin I. Angiotensin I is converted by angiotensin
converting enzyme (ACE) to angiotensin II. The latter is an active
pressor substance which has been implicated as the causative agent
in several forms of hypertension in various mammalian species,
e.g., humans. The compounds of this invention intervene in the
angiotensinogen.fwdarw.(renin).fwdarw.angiotensin
I.fwdarw.(ACE).fwdarw.angiotensin II sequence by inhibiting
angiotensin converting enzyme and reducing or eliminating the
formation of the pressor substance angiotensin II. Thus by the
administration of a composition containing one (or a combination)
of the compounds of this invention, angiotensin dependent
hypertension in a species of mammal (e.g., humans) suffering
therefrom is alleviated. A single dose, or preferably two to four
divided daily doses, provided on a basis of about 0.1 to 100 mg.
per kilogram of body weight per day, preferably about 1 to 15 mg.
per kilogram of body weight per day is appropriate to reduce blood
pressure. The substance is preferably administered orally, but
parenteral routes such as the subcutaneous, intramuscular,
intravenous or intraperitoneal routes can also be employed.
The compounds of this invention can also be formulated in
combination with a diuretic for the treatment of hypertension. A
combination product comprising a compound of this invention and a
diuretic can be administered in an effective amount which comprises
a total daily dosage of about 30 to 600 mg., preferably about 30 to
330 mg. of a compound of this invention, and about 15 to 300 mg.,
preferably about 15 to 200 mg. of the diuretic, to a mammalian
species in need thereof. Exemplary of the diuretics contemplated
for use in combination with a peptide of this invention are the
thiazide diuretics, e.g., chlorthiazide, hydrochlorthiazide,
flumethiazide, hydroflumethiazide, bendroflumethiazide,
methychlothiazide, trichlormethiazide, polythiazide or benzthiazide
as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide,
musolimine, bumetanide, triamterene, amiloride and spironolactone
and salts of such compounds.
The compounds of formula I can be formulated for use in the
reduction of blood pressure in compositions such as tablets,
capsules or elixirs for oral administration, or in sterile
solutions or suspensions for parenteral administration. About 10 to
500 mg. of a compound of formula I is compounded with a
physiologically acceptable vehicle, carrier, excipient, binder,
preservative, stabilizer, flavor, etc., in a unit dosage form as
called for by accepted pharmaceutical practice. The amount of
active substance in these compositions or preparations is such that
a suitable dosage in the range indicated is obtained.
The phosphinylalkanoyl amino acids of formula I can be prepared by
reacting a compound having the formula ##STR9## with a
phosphinyl-acetic or propionic acid having the formula ##STR10## In
formula II and throughout the specification, R.sub.4 ' is alkyl,
arylalkyl or ##STR11## The reaction can be accomplished using known
amide bond forming procedures. For example, the reaction can be run
in the presence of a coupling agent such as
dicyclohexylcarbodiimide, or the acid of formula III can be
activated by formation of its mixed anhydride, symmetrical
anhydride, acid halide (preferably acid chloride) or acid ester, or
by the use of Woodward reagent K,
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline,
N,N'-carbonyldiimidazole or the like. A review of these methods can
be found in Methoden er Organischen Chemie (Houben-Weyl), Vol. XV,
part II, page 1 et seq. (1974). The product of the reaction has the
formula ##STR12##
Compounds of formula I wherein R.sub.2 is hydrogen can
alternatively by obtained by (i) treating a corresponding compound
of formula IV wherein R.sub.2 is alkyl with a halosilane such as
bromotrimethylsilane and then water or (ii) catalytic hydrogenation
of a corresponding compound of formula IV wherein R.sub.2 is
arylalkyl, e.g., using palladium on charcoal. These products have
the formula ##STR13##
Compounds of formula I wherein R.sub.4 is hydrogen, i.e., compounds
having the formula ##STR14## can be obtained by basic hydrolysis of
a compound of formula IV or V. Alternatively, a compound of formula
IV or V wherein R.sub.4 ' is an easily removable ester group (such
as t-butyl) can be treated with trifluoroacetic acid and anisole to
obtain the carboxylic acids of formula I.
The phosphinylalkanoyl amino acids of formula I wherein n is 1 can
alternatively be prepared by reacting a compound of formula II with
a phospholane having the formula ##STR15## The reaction proceeds
most readily when run in the presence of an organic base, e.g.,
triethylamine, pyridine, N,N-dimethylamine or the like, in an inert
organic solvent such as acetonitrile, dichloromethane, ether,
tetrahydrofuran, or the like.
Phosphinyl-acetic or propionic acid derivatives of formula III can
be prepared using known procedures; see, for example, U.S. Pat. No.
4,168,267, issued Sept. 18, 1979. Phospholanes of formula VII can
be prepared following the procedures described in Zh. Obsh. Kim.,
37:411 (1967) and Zh. Obsh. Kim., 38:288 (1968).
The amino acid esters of formula II are known or are readily
obtainable using known esterification techniques which are
illustrated in the examples.
Additional processes for preparing the compounds of this invention
will be apparent to the practitioner of this invention. For
example, the carboxyl group of an amino acid having the formula
##STR16## can be protected, e.g., by conversion to an amine salt,
or a 2-hydroxyethyl or diphenylmethyl ester, reacted with a
phosphinyl-acetic or propionic acid of formula III, and then
deprotected to yield a product of formula VI.
Esterification of a product of formula VI using art-recognized
procedures yields the corresponding product of formula IV.
An alternative procedure for preparing the compounds of this
invention wherein R.sub.2 is alkyl, arylalkyl or ##STR17## and
R.sub.4 is hydrogen comprises first alkylating the corresponding
compound of formula V wherein R.sub.4 ' is benzhydryl or t-butyl,
and then subjecting the resulting compound to ester cleavage with
trifluoroacetic acid and anisole or with other art-recognized
reagents.
The compounds of formula I (wherein --R.sub.5 --COO is a residue of
an amino acid other than glycine) exist in diasteromeric forms or
in racemic mixtures thereof; all are within the scope of this
invention. The L-isomers are preferred.
The compounds of this invention wherein at least one of R.sub.2 or
R.sub.4 is hydrogen, form basic salts with various inorganic and
organic bases which are also within the scope of the invention.
Such salts include ammonium salts, alkali metal salts like lithium,
sodium and potassium salts (which are preferred), alkaline earth
metal salts like the calcium and magnesium salts, salts with
organic bases, e.g., dicyclohexylamine salt, benzathine,
N-methyl-D-glucamine, hydrabamine salts, salts with amino acids
like arginine, lysine and the like. The nontoxic, physiologically
acceptable salts are preferred, although other salts are also
useful, e.g., in isolating or purifying the product. The salts are
formed using conventional techniques.
The following examples are specific embodiments of this
invention.
EXAMPLE 1
N-[[Ethoxy(4-phenylbutyl)phosphinyl]acetyl]-L-tyrosine, methyl
ester
1,1'-Carbonyldiimidazole (0.56 g) was added portionwise to a cooled
(0.degree. C.) solution of [ethoxy(4-phenylbutyl)phosphinyl]acetic
acid (0.98 g) in 70 ml of acetonitrile. This reaction mixture was
stirred under argon at 0.degree. C. for 1.5 hours. The HCl salt of
L-tyrosine methyl ester (0.8 g) was dissolved in methanol and
neutralized with triethylamine (0.35 g). This solution was
concentrated in vacuo, dissolved in 10 ml of warm acetonitrile and
added dropwise to the above solution of activated phosphinic acid
ester sidechain. The reaction was stirred overnight under argon and
then concentrated in vacuo. A solution of the pot residue in
dichloromethane was washed (H.sub.2 O, aqueous NaHCO.sub.3, brine),
dried (MgSO.sub.4) and filtered to yield 1.4 g of
N-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-L-tyrosine, methyl
ester.
EXAMPLE 2
N-[[Hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-tyrosine, methyl
ester
Trimethylsilylbromide (0.5 ml) was added to a cooled solution of
N-[[ethoxy(4-phenylbutyl)-phosphinyl]acetyl]-L-tyrosine, methyl
ester (1.4 g; see example 1) in 50 ml of dichloromethane. This was
stirred under argon for 2 days and then concentrated in vacuo. The
residue was dissolved in 150 ml of ethyl acetate, washed (10%
aqueous NaH.sub.2 PO.sub.4, brine) and dried (MgSO.sub.4). Product
was separated from starting material by extracting the ethyl
acetate solution with three portions of 25% aqueous NaHCO.sub.3.
The bicarbonate solution was acidified with 10% aqueous HCl and
extracted with two 100 ml portions of ethyl acetate containing 5 ml
of isopropanol. This was dried with MgSO.sub.4, filtered and
concentrated in vacuo to yield 0.94 g of analytical product.
Calc. for C.sub.22 H.sub.28 NO.sub.6 P: C, 60.96; H, 6.51; N, 3.23;
P, 7.15, for C.sub.22 H.sub.28 NO.sub.6 P.0.5 H.sub.2 O: C, 59.72;
H, 6.61; N, 3.17; P, 7.0 Found: C, 59.56; H, 6.27; N, 3.00; P,
6.7.
EXAMPLE 3
N-[[Hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-tyrosine
N-[[Hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-tyrosine, methyl
ester (0.86 g; see example 2) was dissolved in 10 ml of methanol.
Sodium hydroxide (0.24 g) in 7 ml of water was added and this was
stirred at room temperature for 4 hours. At the end of this time
period the pH was 10. Methanol was evaporated off and the reaction
mixture was diluted to 20 ml with water, filtered through a
Millipore filter, and the filtrate was acidified with 10%
KHSO.sub.4. The aqueous solution was saturated with salt, extracted
with ethyl acetate, dried (MgSO.sub.4), filtered and concentrated
in vacuo to yield 0.5 g of analytical material.
Calc. for C.sub.21 H.sub.26 NO.sub.6 P: C, 60.28; H, 6.02; N, 3.35;
P, 7.4, for C.sub.21 H.sub.26 NO.sub.6 P.0.25 H.sub.2 O: C, 59.64;
H, 6.08; N, 3.31; P, 7.3, Found: C, 59.44; H, 6.13; H, 3.05; P,
7.1.
EXAMPLE 4
N.sup.2 -[[Ethoxy(4-phenylbutyl)phosphinyl]acetyl]-L-arginine
To a solution of 5 g of [ethoxy(4-phenylbutyl)phosphinyl]acetic
acid in 132 ml of dry dimethylformamide (DMF) at room temperature
under nitrogen was added 2.9 g of 1,1'-carbonyldiimidazole (CDI).
After one hour at room temperature, the reaction mixture was
treated with 3.1 g of L-arginine added as a solid in one portion.
After stirring the reaction mixture overnight under nitrogen, the
DMF was removed in vacuo and the crude reaction mixture was
dissolved in water, acidified to pH 2 with concentrated HCl and
extracted with ether. Work-up of the ether layer gave 1.7 g of the
starting acid. The desired product was isolated by application of
the acidified aqueous extract to an ion exchange column (AG50W-X2)
(H.sup.+)) prepared in water. Initial elution with water removed
the acidic material. When the pH returned to near neutral a
gradient from water to 0.07 M pH 6.5 pyridine-acetic acid buffer
was run. The Sakaguchi positive fractions were pooled and
lyophilized to afford 2.1 g of product. This material was finally
purified on about 500 ml of Sephadex LH-20 resin in water to afford
1.9 g of the title compound, melting point 55.degree.-65.degree.
C.; [.alpha.].sub.D negligible.
Calc'd. for 1.4 H.sub.2 O: C, 51.58; H, 7.75; N, 12.03; P, 6.65,
Found: C, 51.49; H, 7.30; N, 11.95; P, 6.70.
EXAMPLE 5
N.sup.2 -[[Hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-arginine
A solution of N.sup.2
-[[ethoxy(4-phenylbutyl)-phosphinyl]acetyl]-L-arginine (652 mg; see
example 4) in 15 ml of 4 N hydrogen bromide/acetic acid was kept at
room temperature in a stoppered flask overnight. The reaction
mixture was then purged with a stream of nitrogen and repeatedly
treated with water and concentrated on a rotary evaporator.
Lyophilization afforded 1.04 g of crude product. Chromatography on
the weakly acidic carboxymethyl cellulose CM-52(H.sup.+) resin
yielded material which still had 0.75 equivalents of HBr as
indicated by microanalysis. The title compound was finally obtained
pure by passage through ion exchange resin (AG50W-X2 (H.sup.+))
eluted first with water to remove HBr, then finally with 5% aqueous
pyridine to yield a total of 178 mg of product as a white solid
after lyophilization. The product was a 0.7 H.sub.2 O solvate.
EXAMPLE 6
N-[[(2-Phenylethyl)(phenylmethoxy)phosphinyl]-acetyl]-L-tryptophan,
phenylmethyl ester
[(2-Phenylethyl)(phenylmethoxy)phosphinyl]-acetic acid (3.2 g) and
1,1'-carbonyldiimidazole (1.6 g) were stirred in 50 ml of dry
acetonitrile in an ice bath for 1 hour. The free base of
L-tryptophan, benzyl ester derived from 4.8 g of the hydrochloride
salt (from ether/NaHCO.sub.3) was added in a little acetonitrile.
After stirring at 0.degree. C. for 1 hour, the mixture was allowed
to stand at room temperature overnight, taken up in ether, washed
with 5% NaHSO.sub.4, brine, saturated NaHCO.sub.3, brine (2 times),
dried (Na.sub.2 SO.sub.4), and evaporated to dryness yielding 5.7 g
of product. This material was flash chromatographed on LP-1 silica
gel (400 ml) eluted with ethyl acetate and yielded 3.6 g of product
as a slightly colored oil.
Analysis calc'd for C.sub.35 H.sub.31 N.sub.2 O.sub.5 P: C, 70.69;
H, 5.93; N, 4.71; P, 5.21, Found: C, 70.55; H, 5.98; N, 4.65; P,
5.28.
EXAMPLE 7
N-[[Hydroxy-(2-phenylethyl)phosphinyl]acetyl]-L-tryptophan, ammonia
salt
N-[[(2-Phenylethyl)(phenylmethoxy)phosphinyl]-acetyl]-L-tryptophan,
phenylmethyl ester (3.3 g; see example 6) was dissolved in
methanol, and lithium hydroxide monohydrate (0.466 g) dissolved in
a little water was added. The mixture was stirred at room
temperature for 2 hours; 10% palladium on charcoal (1 g) was added
and the mixture hydrogenated at 1 atmosphere for 2 hours. The
catalyst was filtered off through Celite and the filtrate
evaporated to dryness. The residue was dissolved in water, passed
through a Millipore filter, and lyophilized yielding 2.1 g of
product, melting point >350.degree. C., [.alpha.].sub.RT.sup.D
+3.9.degree.[1,H.sub.2 O].
Analysis calc'd for C.sub.21 H.sub.21 N.sub.2 O.sub.5
PLi.sub.2.3H.sub.2 O: C, 52.51; H, 5.67; N, 5.83; P, 6.45; Li,
2.89. Found: C, 52.44; H, 5.03; N, 5.64; P, 6.40; Li, 3.1.
Electrophoresis showed this material to have two components. It
(300 mg) was chromatographed on DEAE sephadex (60 ml) (OH form, pH
7.4) eluted with a NH.sub.4 HCO.sub.3 gradient (0.005 to 0.5 M).
Pure fractions (one component by electrophoresis) were combined and
evaporated. The residue was dissolved in water, Millipore filtered
and lyophilized two times yielding 0.29 g of product,
[.alpha.].sub.RT.sup.D +3.degree.[0.5, H.sub.2 O].
Analysis calc'd for C.sub.21 H.sub.23 N.sub.2 O.sub.5 P(NH.sub.3,
H.sub.2 O): C, 56.12; H, 6.28; N, 9.35; P, 6.87, Found: C, 55.95;
H, 5.90; N, 9.43; P, 6.60.
EXAMPLES 8-24
Following the procedure of examples 4 and 5, but starting with the
compound listed in column I in place of L-arginine, yields the
compound listed in column II. In example 21, it is necessary to use
a protected lysine derivative.
______________________________________ Column I Column II
______________________________________ 8. L-alanine N.sup.2
--[[hydroxy(4-phenylbutyl)- phosphinyl]acetyl]-L-alanine 9.
L-leucine N.sup.2 --[[hydroxy(4-phenylbutyl)-
phosphinyl]acetyl]-L-leucine 10. N--methyl-L- N.sup.2
--[[hydroxy(4-phenylbutyl)- leucine phosphinyl]acetyl]-N--methyl-
L-leucine 11. glycine N.sup.2 --[[hydroxy(4-phenylbutyl)-
phosphinyl]acetyl]glycine 12. L-valine N.sup.2
--[[hydroxy(4-phenylbutyl)- phosphinyl]acetyl]-L-valine 13.
L-isoleucine N.sup.2 --[[hydroxy(4-phenylbutyl)-
phosphinyl]acetyl]-L-isoleucine 14. L-phenylalanine N.sup.2
--[[hydroxy(4-phenylbutyl)- phosphinyl]acetyl]-L-phenyl- alanine
15. L-serine N.sup.2 --[[hydroxy(4-phenylbutyl)-
phosphinyl]acetyl]-L-serine 16. L-threonine N.sup.2
--[[hydroxy(4-phenylbutyl)- phosphinyl]acetyl]-L-threonine 17.
L-cysteine N.sup.2 --[[hydroxy(4-phenylbutyl)-
phosphinyl]acetyl]-L-cysteine 18. L-methionine N.sup.2
--[[hydroxy(4-phenylbutyl)- phosphinyl]acetyl]-L-methionine 19.
L-aspartic N.sup.2 --[[hydroxy(4-phenylbutyl)- acid
phosphinyl]acetyl]-L-aspartic acid 20. L-glutamic acid N.sup.2
--[[hydroxy(4-phenylbutyl)- phosphinyl]acetyl-L-glutamic acid 21.
.epsilon.-t-butoxycar- N.sup.2 --[[hydroxy(4-phenylbutyl)-
bonyl-L-lysine phosphinyl]acetyl]-L-lysine 22. L-asparagine N.sup.2
--[[hydroxy(4-phenylbutyl)- phosphinyl]acetyl]-L-asparagine 23.
L-glutamine N.sup.2 --[[hydroxy(4-phenylbutyl)-
phosphinyl]acetyl]-L-glutamine 24. L-histidine N.sup.2
--[[hydroxy(4-phenylbutyl)- phosphinyl]acetyl]-L-histidine 25.
L-norvaline N.sup.2 --[[hydroxy(4-phenylbutyl)-
phosphinyl]acetyl]-L-norvaline 26. L-norleucine N.sup.2
--[[hydroxy(4-phenylbutyl)- phosphinyl]acetyl]-L-norleucine
______________________________________
EXAMPLE 27
N-[[[(2,2-Dimethyl-1-oxopropoxy)methoxy](4-phenylbutyl)phosphinyl]acetyl]-L
-phenylalanine
(A) [Hydroxy(4-phenylbutyl)phosphinyl]acetic acid, phenylmethyl
ester
A solution of benzyl chloroformate (1.8 ml, 12.6 mmol) in 5 ml of
dry tetrahydrofuran was added dropwise to a solution of
[hydroxy(4-phenylbutyl)phosphinyl]acetic acid (2.55 g, 10 mmol) and
triethylamine (2.0 ml, 14.5 mmol) in 30 ml of dry tetrahydrofuran
at 0.degree. C. After addition was complete, the mixture was
stirred at 0.degree. C. for 30 minutes and at room temperature for
1 hour. The mixture was positioned between ethyl acetate and 5%
KHSO.sub.4 and the ethyl acetate layer was evaporated to a residue.
The residue was taken up in aqueous NaHCO.sub.3, washed with ethyl
acetate, and the aqueous solution acidified to pH 1 and extracted
with ethyl acetate. The extracts were dried (Na.sub.2 SO.sub.4) and
evaporated to give the crude product which was triturated with
pentane to yield a solid, melting point 64.degree.-67.degree. C.
(3.30 g).
(B)
[[(2,2-Dimethyl-1-oxopropoxy)methoxy](4-phenylbutyl)phosphinyl]acetic
acid, phenylmethyl ester
[Hydroxy(4-phenylbutyl)phosphinyl]acetic acid, phenylmethyl ester
(3.30 g, 9.5 mmol) was taken up in 10 ml of dry dimethylformamide
and treated with triethylamine (2.7 ml, 9.5 mmol) and chloromethyl
pivalate (2.8 ml, 19.4 mmol) and stirred at room temperature under
argon for 16 hours. The mixture was diluted with ethyl acetate and
washed with water, 5% KHSO.sub.4, and saturated NaHCO.sub.3, then
dried (Na.sub.2 SO.sub.4) and evaporated to a residue which was
purified by flash chromatography on silica gel using ethyl
acetate-hexane eluant to yield the title diester (3.65 g, 83%) as a
colorless oil. TLC R.sub.F (ethyl acetate/hexane, 1:1)=0.39.
(C)
[[(2,2-Dimethyl-1-oxopropoxy)methoxy](4-phenylbutyl)phosphinyl]acetic
acid
[[(2,2-Dimethyl-1-oxopropoxy)methoxy](4-phenylbutyl)phosphinyl]acetic
acid, phenylmethyl ester (2.95 g, 6.4 mmol) in 75 ml of ethyl
acetate was hydrogenated at 48 psi over 10% palladium on charcoal
catalyst (0.4 g) for 1 hour. The mixture was filtered through
Celite and evaporated to dryness to give the title acid as a
colorless oil which solidified to a solid, melting point
48.degree.-50.degree. C.
(D)
[[(2,2-Dimethyl-1-oxopropoxy)methyl](4-phenylbutyl)phosphinyl]acetic
acid, N-hydroxy succinimide ester
[[(2,2-Dimethyl-1-oxopropoxy)methoxy](4-phenylbutyl)phosphinyl]acetic
acid (2.22 g, 6 mmol), N-hydroxy succinimide (0.69 g, 6 mmol), and
dicyclohexylcarbodiimide (1.24 g, 6 mmol) were dissolved in dry
tetrahydrofuran at 0.degree. C. The mixture was stirred overnight
at room temperature, filtered and the filtrate concentrated in
vacuo to an oily residue which was triturated with diisopropyl
ether, yielding a solid, melting point 102.degree.-105.degree. C.
(2.1 g).
(E)
N-[[[(2,2-Dimethyl-1-oxopropoxy)methoxy]-(4-phenylbutyl)phosphinyl]acetyl]
-L-phenylalanine
L-Phenylalanine (1.65 g, 10 mmol), triethylamine (2.8 ml, 20 mmol)
and
[[(2,2-dimethyl-1-oxopropoxy)methoxy]-(4-phenylbutyl)phosphinyl]acetic
acid, N-hydroxy succinimide ester (4.67 g, 10 mmol) are dissolved
in 50 ml of dry dimethylformamide and stirred overnight under argon
at room temperature. The reaction mixture is partitioned between
dichloromethane and 5% KHSO.sub.4, and the organic layer is washed
with water and brine and then dried and evaporated to yield the
desired product.
EXAMPLES 28-34
Following the procedure of example 27, but substituting the
compound in column I for [hydroxy(4-phenylbutyl)phosphinyl]acetic
acid, the compound in column II for chloromethyl pivalate and the
compound in column III for L-phenylalanine, yields the compound
listed in column IV.
__________________________________________________________________________
Column I Column II Column III
__________________________________________________________________________
[hydroxy(4-phenylbutyl)]- chloromethyl L-alanine
N--[[[(2,2-dimethyl)-oxopropoxy)- phosphinyl acetic acid pivalate
methoxy](4-phenylbutyl)phosphinyl] acetyl]-L-alanine
[hydroxy(4-phenylbutyl)- acetic acid, L-phenylalanine
N--[[[1-(acetyloxy)ethoxy](4-phenyl- phosphinyl]acetic acid
1-chloroethyl butyl)phosphinyl]acetyl]-L-phenylalanine ester 30.
[hydroxy(2-phenylethyl)- isobutyric L-tryptophan
N--[[[(2-Methyl-2-oxopropoxy)methoxy- phospninyl]acetic acid acid,
chloro- 4-phenylbutyl)phosphinyl]acetyl]-L- methyl ester tryptophan
[hydroxy(4-phenylbutyl)- carbonic acid, L-phenylalanine
N--[[[(ethoxycarbonyloxy)methoxy]- phosphinyl]acetic acid ethyl
chloro- (4-phenylbutyl)phosphinyl]acetyl]-L- methyl diester
phenylalanine [hydroxy(octyl)phos- propionic acid, L-tyrosine
N--[[octyl[1-(1-oxopropoxy)ethoxy]- phinyl]acetic acid
1-chloroethyl phosphinyl]acetyl]-L-tyrosine [hexyl(hydroxy)phos-
1-chloroethyl L-methionine N--[[[1,(2,2-dimethyl-1-oxopropoxy)-
phinyl]acetic acid pivalate ethoxy](hexyl)phosphinyl]acetyl]-L-
methionine [hydroxy(4-phenylbutyl)- 1-chloroethyl L-arginine
N--[2-methyl-1-oxo-[[1-(1-oxopropoxy)- phosphinyl]-.alpha.-methyl-
pivalate ethoxy](4-phenylbutyl)phosphinyl]- propionic acid
propyl]-L-arginine
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* * * * *